Differential regulation of SOCS genes in normal and transformed erythroid cells

• Published in: Oncogene Vol. 22; no. 21; pp. 3221 - 3230
• Main Authors: SARNA, Mohinder K, INGLEY, Evan, ALEXANDER, Warren S, HILTON, Douglas J, STARRY, Robyn, WATOWICH, Stephanie S, BITTORF, Thomas, KLINKEN, S. Peter, TILBROOK, Peta A, BUSFIELD, Samantha J, CULL, Vanessa S, LEPERE, Winald, MCCARTHY, David J, WRIGHT, Michael J, PALMER, Gene A, CHAPPELL, David, SAYER, Melissa S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 22-05-2003; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Cancer; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Carrier Proteins - physiology; Cell Differentiation; Cell Line, Transformed; Cells, Cultured; Cytokines; Ectopic expression; Erythrocytes; Erythroid cells; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - metabolism; Erythropoietin; Erythropoietin - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Growth factors; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - genetics; Intracellular signalling; Kinases; Medical research; Mice; Molecular and cellular biology; Mutation; Progenitor cells; Promoter Regions, Genetic; Protein Biosynthesis; Protein-tyrosine kinase; Proteins - genetics; Receptors, Erythropoietin - genetics; Repressor Proteins; RNA, Messenger - biosynthesis; Signal transduction; src-Family Kinases - metabolism; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors; Transcriptional Activation; Tumor suppressor genes; Tumors; Australia; Genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206381

The SOCS family of genes are negative regulators of cytokine signalling with SOCS-1 displaying tumor suppressor activity. SOCS-1, CIS and SOCS-3 have been implicated in the regulation of red blood cell production. In this study, a detailed examination was conducted on the expression patterns of these three SOCS family members in normal erythroid progenitors and a panel of erythroleukemic cell lines. Unexpectedly, differences in SOCS gene expression were observed during maturation of normal red cell progenitors, viz changes to CIS were inversely related to the alterations of SOCS-1 and SOCS-3. Similarly, these SOCS genes were differentially expressed in transformed erythoid cells - erythroleukemic cells immortalized at an immature stage of differentiation expressed SOCS-1 and SOCS-3 mRNA constitutively, whereas in more mature cell lines SOCS-1 and CIS were induced only after exposure to erythropoietin (Epo). Significantly, when ectopic expression of the tyrosine kinase Lyn was used to promote differentiation of immature cell lines, constitutive expression of SOCS-1 and SOCS-3 was completely suppressed. Modulation of intracellular signalling via mutated Epo receptors in mature erythroleukemic lines also highlighted different responses by the three SOCS family members. Close scrutiny of SOCS-1 revealed that, despite large increases in mRNA levels, the activity of the promoter did not alter after erythropoietin stimulation; in addition, erythroid cells from SOCS-1-/- mice displayed increased sensitivity to Epo. These observations indicate complex, stage-specific regulation of SOCS genes during normal erythroid maturation and in erythroleukemic cells.